Chemical reaction cartridge, its fabrication method, and a chemical reaction cartridge drive system

ABSTRACT

The present invention describes a disposable chemical reaction cartridge comprising a container formed of a rigid substrate and an elastic body, wherein two or more chambers are linked or configured to be linked through flow paths, and wherein the flow paths, the chambers or both, can be partially closed by applying an external force to the elastic body from outside of the container, to move or block fluids in the flow paths or chambers. The cartridge has a structure protected against viruses or dangerous drugs and facilitates foolproof implementation of prescribed protocols for the samples to be tested.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to chemical reaction cartridges, moreparticularly, the chemical reaction cartridges wherein synthesis,dissolution, detection, separation or the like of solution can beperformed easily according to prescribed protocols without differencesamong operators at low cost.

2. Description of the Prior Art

Conventionally, test tubes, beakers, pipettes or the like have beengenerally used for processing such as synthesis, dissolution, detection,separation or the like of solution. For example, as shown in FIG. 1,substance A and substance B are collected in container 1 and container 2respectively such as test tubes or beakers. Then, these substances areadded to container 3 such as a test tube or a beaker, wherein thesesubstances are mixed or disturbed to create substance C. Substance Csynthesized in this manner is observed, for example, in terms of lightemission, heat generation, color change, color comparison, or the like.

Alternatively, a mixed substance is percolated, centrifugally separatedor the like to separate and extract a target substance.

Also, glassware such as a test tube or a beaker is used for treatmentssuch as dissolution, for example, by means of organic solvent. Also inthe case of detection processing, as in FIG. 1, substance A under testin container 1 and a reagent in container 2 are injected into container3 to observe their reaction results.

On the other hand, for devices such as bioanalyzers, for example, bagsformed in a flat pouch shape using flexible materials as described inthe Japanese Unexamined Patent Application No. 2002-365299, are used.

FIG. 2 is a configuration drawing of a biochip as described in theabove-mentioned Japanese Unexamined Patent Application No. 2002-365299.FIG. 2( a) is a cross-sectional view. FIG. 2( b) is a plan view. Thecenter part of flat blood collection bag 41 which is sealed at itsperiphery is in a pisciform pouch. The opening of the pisciform pouch issealed with rubber plug 42.

In blood collection bag 4l, collection block 43, preprocessing area 44,junction 45, and waste liquid reservoir 47 are formed in order from thisplug 42 towards the back. For blood collection, plug 42 is inserted intoa syringe (not illustrated), wherein a syringe needle is projected topenetrate plug 42.

For blood collection, plug 42 is inserted into a syringe (notillustrated). A syringe needle is projected in the syringe to penetrateplug 42.

For blood collection, the tip of the needle projected externally fromthe syringe is inserted into a person under test. Hooks 52 and 53 ofblood collection bag 41 are pulled out to collect blood in collectionblock 43. After blood collection, the syringe is withdrawn from bloodcollection bag 41. Then, as shown in FIG. 3, blood collection bag 41 issandwiched between rotating rollers 61 and 62 to squash the biochip fromcollection block 43 towards preprocessing area 44. The collected bloodis sent to preprocessing area 44.

When rollers 61 and 62 proceed and start squashing pocket 48, solutionin pocket 48 breaks valve 49 and flows into preprocessing area 44. Next,solution in pocket 50 flows into preprocessing area 44 in the samemanner. When the prescribed processing in preprocessing area 44 ends,the rollers are rotated to send the processed blood to junction 45.

DNA chip 46 is arranged in junction 45 to perform hybridization. Theextra blood or solution pressed out from preprocessing area 44 is storedin waste liquid reservoir 47. Conditions of DNA chip 46 whereinhybridization is performed are observed by means of a reading apparatusarranged externally.

However, conventional methods using beakers, pipettes or the like haveproblems such as complicated operations, large differences amongoperators, and a large amount of time and effort required.

In addition, blood collection bags have the problem that it is not easyto move solution because these bags lack elasticity.

SUMMARY OF THE INVENTION

An object of the present invention is to realize a chemical reactioncartridge, which enables prescribed protocols to be achieved easilywithout differences among operators, is sealed and disposable, and has asafe structure against viruses or dangerous drugs, as well as to realizeits fabrication method and a chemical reaction cartridge drive system.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates a prior art processing method.

FIG. 2 is a configuration diagram of a prior art blood collection bag.

FIG. 3 illustrates an operation method of the blood collection bag.

FIG. 4 is a configuration diagram of an embodiment of a chemicalreaction cartridge concerning the present invention.

FIG. 5 illustrates an operating state.

FIG. 6 exemplifies another operating state.

FIG. 7 is a configuration diagram of another embodiment of the presentinvention.

FIG. 8 illustrates an embodiment concerning a flow path pressurizationmethod.

FIG. 9 illustrates another embodiment concerning a flow pathpressurization method.

FIG. 10 illustrates yet another embodiment concerning a flow pathpressurization method.

FIG. 11 is a configuration diagram of yet another embodiment of thepresent invention.

FIG. 12 illustrates a pressurization method.

FIG. 13 illustrates a concrete example of a shape of a flow path.

FIG. 14 illustrates another pressurization method.

FIG. 15 illustrates yet another pressurization method.

FIG. 16 illustrates yet another pressurization method.

FIG. 17 is a configuration diagram of yet another embodiment of thepresent invention.

FIG. 18 illustrates a shape of a flow path or a chamber.

FIG. 19 illustrates an elastic body having a layered structure.

FIG. 20 illustrates a detection method of a reaction chamber.

FIG. 21 is a configuration diagram of yet another embodiment of acartridge.

FIG. 22 is a configuration diagram of yet another embodiment of acartridge.

FIG. 23 is a configuration diagram of yet another embodiment of acartridge.

FIG. 24 is a configuration diagram of an embodiment of an inlet of acartridge.

FIG. 25 is a diagram related to the materials of a substrate.

FIG. 26 illustrates a method concerning injection and junction.

FIG. 27 is a configuration diagram of yet another embodiment of acartridge.

FIG. 28 is a configuration diagram of yet another embodiment of acartridge.

FIG. 29 illustrates a sucking method for samples.

FIG. 30 is a configuration diagram of yet another embodiment of acartridge.

FIG. 31 illustrates an embodiment of a shape of a chamber.

FIG. 32 illustrates a subject to be treated.

FIG. 33 illustrates an embodiment which enables cell homogenization.

FIG. 34 is a configuration diagram of yet another embodiment of acartridge.

FIG. 35 is a configuration diagram of yet another embodiment of acartridge.

FIG. 36 is a configuration diagram of yet another embodiment of acartridge.

FIG. 37 illustrates an embodiment concerning a junction between anelastic body and a substrate.

FIG. 38 is a configuration diagram of yet another embodiment of acartridge.

FIG. 39 is a configuration diagram of an embodiment of a chemicalreaction cartridge concerning the present invention.

FIG. 40 is a configuration diagram of another embodiment of a chemicalreaction cartridge concerning the present invention.

FIG. 41 is a configuration diagram of yet another embodiment of achemical reaction cartridge concerning the present invention.

FIG. 42 illustrates yet another embodiment of a flow path pressurizationmethod.

FIG. 43 illustrates yet another embodiment concerning a flow pathpressurization method.

FIG. 44 illustrates an embodiment wherein six flow paths are formed forone chamber, while three open/close valves are formed.

FIG. 45 illustrates another embodiment of a shape of a roller.

FIG. 46 illustrates yet another embodiment of a shape of a roller.

FIG. 47 illustrates an example of using a roller with convex parts.

FIG. 48 illustrates a principal portion of an embodiment of a chemicalreaction cartridge concerning the present invention.

FIG. 49 illustrates a principal portion of another embodiment of thepresent invention.

FIG. 50 illustrates a principal portion of yet another embodiment of thepresent invention.

FIG. 51 illustrates a principal portion of yet another embodiment of thepresent invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention is now explained in detail with reference to thedrawings. FIG. 4 is a configuration diagram of an embodiment of achemical reaction cartridge concerning the present invention. FIG. 4( a)is a perspective view. FIG. 4( b) is a bottom view of an elastic body.FIG. 4( c) is a Z-Z′ cross-sectional view. Chemical reaction cartridge100 comprises elastic body 110 made of sealed elastic rubber or the likeand tabular substrate (rigid body substrate) 120 made of hard materialsfor the purpose of position determination and shape maintenance.

A viscoelastic body or a plastic body may be used for elastic body 110for a cartridge (however, an elastic body is used as an example of theembodiment).

Holes for solution (hereinafter called “chamber”) 111 and 112, each ofwhich is concave towards the surface, a chamber for reaction (alsocalled “a reaction chamber”) 113, a chamber for storing waste liquid(also called “a waste liquid reservoir”) 114, and a flow path 115linking these chambers are formed on the back of elastic body 110, asshown in FIG. 4( b).

Elastic body 110 and tabular adhesion area 116 excluding the flow pathare adhered to the surface of substrate 120, as shown in FIG. 4( c),thereby creating a structure wherein chambers and the flow path aresealed by elastic body 110 and substrate 120 to prevent solution fromleaking externally.

Next, transfer of solution in a cartridge with such a structure isexplained. Substance (hereinafter called “solution” because solution isused as an example) A and solution B are injected in advance intochambers 111 and 112, which are formed on cartridge 100. Solution isinjected by means of syringe 118 after syringe needle 117 is directlyinserted into elastic body 110, as shown in FIG. 4( c). Since elasticbody 110 is formed of elastic materials, the needle hole self-closes ifsyringe needle 117 is withdrawn. In order to seal the hole completely,the needle hole is filled with adhesive agent or the like after solutionis injected. However, the hole may be sealed by means of heateddissolution.

As FIG. 5 shows, roller 130 is pressed downward from above at the leftend of cartridge 100 to the extent that chamber 111 is squashed. Then,if roller 130 is rotated and moved from position 1 to the rightdirection as shown in FIG. 6( a), solution A stored in chamber 111 ispressed out to the right direction. Solution A is sent through flow path115 into reaction chamber 113. The air in chamber 113 is sent out towaste liquid reservoir 114.

If roller 130 is continuously rotated and moved to position 2 as shownin FIG. 6( b), solution B in chamber 112 is sent out. Solution B ispressed out through flow path 115 into reaction chamber 113. On thisoccasion, the halfway portion of flow path 115 is also squashed whenroller 130 is pressed downward, which in turn becomes a valve to stopflow-back, thereby preventing solution B from flowing back to chamber111.

When solution A and solution B enter reaction chamber 113, they aremixed and react. Reaction here means, for example, mixture, synthesis,dissolution, separation or the like.

Use of these cartridges enables detection of, for example, dioxin, DNAor the like.

In addition, if roller 130 is rotated and moved to position 7 in thereverse direction as shown in FIG. 6( d) after roller 130 is rotated andmoved from position 3 to position 6 as shown in FIG. 6( c), solution canbe easily mixed.

Usually, roller 130 ends a rotary movement in one direction (in onepath).

These cartridges can be fabricated to be small in size, light in weightand low in cost. Also, treatment protocols such as mixture, synthesis,dissolution, separation or detection of substances can be performedeasily in these cartridges without differences among operators.

In addition, a cartridge of the present invention is sealed anddisposable. It can handle viruses, dangerous drugs or the like safely.For example, treatments (a series of treatments such as neutralization,distillation, sampling, mixing, and calorimetric detection) of wastewater from factories, concentration waste water or detection of cyanogenin rivers or the like into which such waste water flows, extraction ofDNA or protein from blood streams or diseased parts, or the like can beperformed in this cartridge safely and reliably.

Note that these explanations are only intended to show certainappropriate embodiments in order to exemplify the present invention.Therefore, it is to be understood that the present invention is notrestricted to the foregoing embodiments. Rather, many other alterationsand modifications thereof may be made without departing from the spiritand essential characteristics thereof:

(1) As shown in FIG. 7, not only chambers 111 and 112 for solutions Aand B respectively but also chambers 141 and 142 leading to flow path115 may be formed for the purpose of storing cleaning liquid or dryingair.

(2) Downward pressurization of the flow path by means of an externalforce outside a cartridge may be performed not only by a roller but alsoby an actuator which applies force in a vertical direction to syringe151 as shown in FIG. 8, wherein chamber 112 shown in FIG. 7 or the likemay also be pressed directly by the actuator so that solution in chamber112 can be pressed out.

(3) As shown in FIG. 9, a plurality of actuators may be used to realizepumping, wherein solution 153 can be pressed out into the direction ofthe arrow (right) if wide syringe 152 is pressed down after syringe 151is pressed down.

(4) As shown in FIG. 10, if a plurality of actuators with capability tocontrol individual actions are arranged in a matrix and are presseddown, they can also be used for cartridges with general-purpose flowpaths.

(5) Convex part 161 is formed on the surface of elastic body 110immediately above a flow path, as shown in FIGS. 11( a), (b), and (c).Even if widths, shapes or the number of flow paths change, they can besquashed and sealed reliably, where in rigid substrate 120 is veryhelpful in maintaining positions accurately.

(6) If the width of a roller is smaller than that of a cartridge,peripheral areas of elastic body 110 may tend to camber as shown in FIG.12( a), wherein peripheral areas should be pressed in advance by meansof pressing frame 171 as shown in FIG. 12( b).

(7) As shown in FIG. 13( a), a substantially narrow connecting partbetween a chamber of elastic body 110 and a flow path is formed, whichmakes it easier for solution in the chamber to exit, but which does notallow solution in the flow path to enter the chamber due to such factorsas viscosity resistance. Or, as shown in FIG. 13( b) or (c), a filmvalve may be formed for the connecting part. Or, as shown in FIG. 13(d), the valve may be broken by the pressure of solution in the chamberso that the solution is pressed out.

(8) Pressurization member 180 with the shape of its center expanding(curved) like a barrel may be used instead of a cylindrical roller, asshown in FIG. 14. Or, as shown in FIG. 15, pressurization member 190 ina ball shape may be used. Or, as shown in FIG. 16, pressurization member200 based on an absorbent blotting paper method in a circular arc shapeof a large radius of curvature may be used. Solution can be pressed outin the direction of the arrow if pressurization member 200 is rotated inthe right direction as shown in FIG. 16.

(9) As shown in FIG. 17( a), if reaction chamber 113 is formed thinlyfrom the beginning to expand in the thickness direction when pressure isapplied, there is no need to drain the air of reaction chamber 113.Thus, a chamber for storing waste liquid does not have to be provided inelastic body 110 of cartridge 100.

(10) With respect to the cross-sectional shape of flow path 115 (or achamber), if corners are right-angles as shown in FIG. 18( a), flow path115 is squashed when pressed from above as shown in FIG. 18( b), whilesolution tends to remain at the corners. Thus, as shown in FIG. 18( c),the corners are provided a curvature of a radius R. If flow path 115 hasa height H and a width W, R is desirably one-tenth or more of H or W. Asshown in FIG. 18( d), it is desirable that a corner of a joint withsubstrate 120 should also have a curvature of radius R, as shown in FIG.18( d).

(11) The wall surface of flow path 115 may be given a surface treatmentto provide a hydrophobic surface if solution is soluble in water or toprovide a hydrophilic surface if solution is oily, so that adhesion ofsolution is prevented. Or, Teflon (registered trademark) coating may beprovided, or Teflon (registered trademark) rubber may be used asmaterials for elastic body 110.

(12) Elastic body 110 may have two or more layers. For example, as FIG.19 schematic drawing shows (FIG. 19( a) is a bottom view of elastic body110 and FIG. 19( b) is a cross-sectional view of elastic body 110),chambers 210 and 211 are formed in the first layer 110 a, while chamber220 is formed in the second layer 110 b. In addition, flow path 212 isformed for chamber 210 of the first layer 110 a for connection tochamber 220 of the second chamber 110 b, thereby making chambersthree-dimensional in a compact manner.

(13) Reaction chamber 113 is formed so that it is possible to detectlight, voltage, current, heat or the like of reaction substances. Forexample, a whole elastic body is made transparent or non-transparent(opaque) to light. Or, only an optical measurement portion is madetransparent. If portions other than the optical measurement portion aremade opaque, reagents stored in chambers are protected against light.Or, the whole elastic body may be formed of an insulating body wherein aportion is formed of a conductive elastic body (containing carbon or thelike).

In order to observe light emitted from a reaction substance, as shown inFIG. 20( a), elastic body 110 is formed of transparent materials whereinobservations are conducted by reading means 230, which reads lightemitted from the reaction substance. Elastic body 110 does not have tobe transparent entirely. Instead, it is sufficient that only an opticalmeasurement portion is transparent. Here, a glass chamber or the likecan be embedded.

If voltage or current is detected or if electrophoresis is conducted, asshown in FIG. 20( b), conductors 231 and 232 are arranged to pick updetection signals directly from reaction chamber 113. Or, as shown inFIG. 20( c), electrodes 233 and 234 may be inserted from outside whennecessary.

(14) As shown in FIG. 21, outlet 235 is provided for elastic body 110 inorder to establish a structure wherein a reaction substance can bepressed out from outlet 235 to the outside by means of downwardpressurization of roller 130. In this case, it is desirable that onlysafe substances should be used as reaction substances to be drained.

(15) As shown in FIG. 22, taper 241 in a circular arc shape may beprovided to the upper surface of elastic body 110, wherein solution issent out in the direction of the arrow if tabular pressing plate 240 isvertically pressed down from above.

(16) As shown in FIG. 23, pressing cover 242 and substrate 120 can bejoined by means of hinge 243 so that pressing cover 242 can be freelyopened or closed, thereby being able to send out solution when pressingcover 242 is closed.

(17) Concave part 250 is formed at an inlet for injecting samples asshown in FIG. 24. When syringe needle 117 is inserted or withdrawn, aninjectant is leaked and adhered to the injection inlet. However, asshown in FIG. 24( b), leaked injectant 251 remains in the back ofconcave part 250 due to the injectant's viscosity or surface tension andcannot be drained out of the cartridge. This is useful when injectionliquid (such as blood) itself is hazardous. Withdrawal trace 252 ofsyringe needle 117 is automatically closed.

(18) An elastic body is made of materials such as silicone rubber, PDMS(polydimethylsiloxane), natural rubber and its polymer, acrylic rubber,urethane rubber, or the like. These materials do not have to beperfectly elastic bodies and can be resins having viscoelasticcharacteristics or plastic bodies such as gel. If a material deformsalmost plastically, it is difficult for a gap to be caused even in thecase of FIG. 18( b).

(19) As materials for substrate 120, glass, metals, hard resins, rigidbodies that can be bent, or the like can be used. If a rigid body whichcan be bent is used, a cartridge is placed on a hard plate or table 260to use roller 130 for applying pressure or cartridge 100 is sandwichedbetween two rollers 130 from above and from below, as shown in FIG. 25(a) and FIG. 25( b).

(20) In order to seal an injection inlet after solution is injected intochamber 111, chamber 112, or the like, heat or adhesive agent can beused.

Or, as shown in FIG. 26( a) and FIG. 26( b), elastic body 110 is placedupside down, wherein a chamber is turned upward and solution is injectedinto the chamber. After that, substrate 120 is used to cover thechamber, as shown in FIG. 26( b).

(21) Elastic body 110 and substrate 120 can be joined by means ofabsorption (in the case of PDMS, glass or the like), ultrasonic wave,heating, plasma treatment, vibration or the like, in addition toadhesion.

(22) Substances applicable to testing in cartridges are biologicalmolecules, organic matters, inorganic matters or living organisms suchas bacteria, diseased parts, cells or the like.

(23) For extraction processing in a reaction chamber, magnetic beds,silica beads, silica filters, monolith filters, antibodies, enzymes,dendrimers or the like can be used as extraction means. Note thatvibration to disperse magnetic beads is given by a source of vibration,which is applied, for example, to the outside of a cartridge.

(24) For safety, it is desirable that a solidification reactant shouldbe injected into a waste liquid reservoir in advance.

(25) Since a rigid substrate is affixed to a cartridge, it is possibleto determine an accurate position when external force is applied or whenmeasurements are conducted. Moreover, as shown in FIG. 27( a), a hook orhole 270 for the hook may be provided for fixing a position when a forceis applied from outside. FIG. 27( b) is a side view (cross-sectionalview) when a cartridge is fixed to workbench 271 in such a way that hole270 in FIG. 27( a) is aligned to stopping pin 272 which is mounted toworkbench 271.

In addition, as shown in FIG. 28, positioning mark 273 may be providedfor such activities as measurements.

(26) Samples may be injected using roller 130 as shown in FIG. 29. Inother words, as shown in FIG. 29( a), after syringe needle 117 isinserted, roller 130 pressed downward as in FIG. 29( b) is moved inrotation from the injection inlet towards the back, thereby enabling asample to be sucked into chamber 111 [FIG. 29( c)].

After the sample is sucked, syringe needle 117 is withdrawn as shown inFIG. 29( d), roller 130 is lifted upward and is returned to the originalposition, or a second roller separately provided is pressed, to send thesucked sample towards the back.

If the viscosity of the sample is large enough, the non-return valveeffect of the roller is utilized at the position in FIG. 29( d) to sendthe sample in the cartridge, without withdrawing syringe needle 117.

(27) For the above-mentioned mixing, projection (or wall) 280 may beprovided in chamber 113 for separation and disturbance as shown in FIG.30.

(28) Shapes of chambers may be polygons such as hexagon, rhombus,circular form or the like, as shown in FIGS. 31( a), 31(b), and 31(c).

(29) A cartridge concerning the present invention can handle not onlysolution but also biological cells. As shown in FIG. 32, a target cellis placed in reaction chamber 113, wherein a medical agent stored inanother chamber is supplied and given to the cell, thereby enablingobservations of cell culture or reaction.

A cartridge concerning the present invention can also be used tosynthesize proteins of cell-free systems.

(30) Projection 290 in a triangular shape with its surface having bladesas shown in FIG. 33( a) is mounted on substrate 120. Then, as shown inFIG. 33( b), roller 130 is moved from left to right and vice versa, sothat cells in chamber 113 are homogenized by means of the grindingblades.

(31) The present invention has, for example, the following applications:

-   -   (a) a glucose sensor to determine the concentration of glucose        in blood, wherein a cartridge is a sealed type and enables safe        tests;    -   (b) measurements of NOx or dioxin;    -   (c) detection of microelements such as cadmium, cyanide arsenide        and mercury in hair, water or food, wherein a cartridge is a        sealed type and enables safe detection of agricultural        chemicals, poisonous substances or the like using such methods        as colorimetry;    -   (d) detection or identification of biopolymers such as DNA or        RNA using a hybridization method, or detection or identification        of proteins using antigen-antibody reactions;    -   (e) detection or identification of DNA, RNA or proteins using an        electrophoresis method during detection;    -   (f) detection of molecules using chromatography methods such as        HPLC;    -   (g) detection of molecules based on spectroscopy using        ultraviolet light, visible light or the like;    -   (h) measurements of chemical reactions or changes of substances        using electrochemical measurement methods, i.e., measurements to        qualitatively or quantitatively detect chemical reactions such        as oxidization-reduction reactions of substances or changes in        conductivity ratio using electrochemical measurement methods        such as the impedance method; and    -   (i) detection or separation of cells, blood platelets or the        like by identifying cells such as lymphocytes through        fluorescence or the like using a flow site meter method.

(32) For amplification of PCR (Polymerase Chain Reaction) of genes,metal 300 can be embedded into substrate 120 as shown in FIG. 34,wherein increase or decrease of temperature of this metal 300 iscontrolled by means of Peltier heater 310, thereby facilitating heatexchange and simple PCR amplification.

(33) As shown in FIG. 35, small pressurization mechanism 320 such as arigid body, a PZT, a shape-memory metal alloy, an actuator or the likecan be buried into cartridge 100, wherein pressurization mechanism 320is driven in conjunction with external pressure from actuator 321 or thelike to apply downward pressure and to close a flow path partially.

(34) For using light to detect reaction substances in reaction chamber113, optical waveguide 330 buried in cartridge 100 may be used as shownin FIG. 36.

(35) The shape of an original elastic body or substance of a cartridgecan be fabricated using processing technologies such as milling, lightmolding, and wet or dry etching. Chambers may be fabricated by means ofnot only sheet adhesion as shown in FIG. 4 but also injection molding intheir entirety. Molds for injection molding are fabricated using suchmethods as milling, light molding or etching.

(36) Elastic body 110 and substrate 120 can be sealed not only throughadhesion but also through elastic deformation or in an engagementstructure. In the case of an engagement structure as shown in FIG. 37,complementary teeth 341 and 342 in a right triangular shape are formedat end faces of a joint area between elastic body 110 and substrate 120as shown in FIG. 37( a). These teeth are engaged together as shown inFIG. 37( b). Note that these teeth are formed on entire surroundingareas of a flow path or a chamber.

Such an engagement has a characteristic that it is difficult for elasticbody 110 to expand horizontally when elastic body 110 is pressed down.If projections are provided along a chamber or a flow path as shown inFIG. 37( c), the chamber or the flow path can be sealed easily.

In addition, an external force to partially close the flow path or thechamber and to move or block fluid substance in the flow path or thechamber can be not only a mechanical force but also air pressure.

Moreover, taper 350 may be formed at a location (entrance) of acartridge, wherein a cylindrical roller is joined first, as shown inFIG. 38. If taper 350 is provided, it is sufficient for roller 130 tomove only in one direction, i.e., the right direction as shown in FIGS.38( a) and 38(b), in order to move solution to the right direction. If acartridge does not have a taper entrance, roller 130 needs to move intwo directions, i.e., the downward direction and the right direction, asshown in FIGS. 38( c), 38(d), and 38(e).

FIG. 39 illustrates another embodiment of the present invention. FIG.39( a) is a plan view, FIG. 39( b) is a partial cross-sectional view ofchambers (A, B, C, E, and G) and convex parts (the shaded portions ofFIG. 39( a)), and FIG. 39( c) is a Z-Z′ cross-sectional view. For thepurpose of simplification, a chamber for solution A is called chamber A,while a chamber for solution B is called chamber B (hereinafter, thesame principle applies to C, E, and G).

Note that chemical reaction cartridge 100 is, as in the case of theabove-mentioned embodiment, formed by elastic body 110 (such as sealedand elastic rubber) and tabular substrate 120 (which is formed by rigidmaterials). Materials of substrate 120 and the junction between elasticbody 110 and substrate 120 are also the same as in the case of theabove-mentioned embodiment.

Chambers A through F for solution, each of which is concave towards thesurface, are formed on the back of elastic body 110, as in FIG. 39( b).Convex part 161 is formed on the upper part of the parts of chambers (A,B, C, E, and G), which are concave towards the surface (this convex partis shaded in FIG. 39( a)).

Blood is injected into chamber A, a solution reagent for dissolvingblood is injected into chamber B, and magnetic beads for capturingbiopolymers such as DNA are injected into chamber C. Chamber D is areaction chamber, wherein magnetic field is applied (not illustrated).Cleaning liquid is injected into chamber E, while buffer liquid isinjected into chamber G. Chamber H is a finished product chamber tocontain liquid which is reacted in reaction chamber D. Chamber F is awaste liquid reservoir.

Flow path 115 is formed for these chambers in order to link them.Chambers A and B, which are formed in an area where a convex part isformed (hereinafter called “a convex area”), are linked to chamber C,which is also formed in the convex area, through flow paths 115 a and115 b. Chamber c is linked to chamber D, which is an area without aconvex part (hereinafter called “a concave area”), through flow path 115c. In addition, chambers E and G, which are formed in the convex area,are linked to chamber D through flow paths 115 d and 115 e. Moreover,chamber H formed in the concave area is linked to chamber D through flowpath 115 f formed in the convex area. Chamber F formed in the concavearea is linked to chamber D through flow path 115 g formed in the convexarea.

Each chamber of elastic body 110 and the flat part other than flow pathsare adhered to a surface of substrate 120, as shown in FIG. 39( c),thereby allowing chambers and flow paths to be sealed by elastic body110 and substrate 120, which in turn enables a structure whereinexternal leakage of solution is prevented.

Next, solution transfer operations in cartridges of the above structureare explained.

As mentioned earlier, blood, a solution reagent, cleaning liquid, andbuffer liquid are pre-injected into chambers A, B, E, and G respectivelywhich are formed in cartridge 100. Magnetic beads with surfaces to carrypositive electrical charges are pre-injected into chamber C. Injections(not illustrated) are performed by means of, for example, a syringewhose needle is directly inserted into elastic body 110. Since elasticbody 110 is formed by elastic materials, the needle hole self-closes ifthe syringe needle is withdrawn. While the needle hole is filled with anadhesive agent or the like to completely seal the hole after solution isinjected, the hole can also be sealed by means of heated dissolution.

In the above configuration, as shown in FIG. 39( d), roller 130 ispressed downward from the above at the left end of cartridge 100 to theextent that the convex area is squashed, wherein blood and the reagentsolution pre-injected into chambers A and B respectively are pushed outin the right direction if roller 130 is rotated and moved from position1 to position 2 in the right direction as shown in FIG. 39( a).

As a result, the blood pre-injected into chamber A is flown through flowpath 115a into chamber C wherein magnetic beads are pre-injected, whilethe reagent solution pre-injected into chamber B is flown through flowpath 115b into chamber C, wherein the blood and the reagent solution aremixed. DNA in the blood is captured on the surfaces of the magneticbeads in chamber C.

Next, roller 130 is rotated and moved from position 2 to position 3 sothat the blood, reagent solution and magnetic beads mixed in chamber Care moved through flow path 115 c to chamber D. Magnetic field isapplied in chamber D, wherein magnetic beads are captured.

Next, roller 130 is rotated and moved from position 3 to position 4 sothat flow path 115f is squashed to block the flow into chamber H.Moreover, roller 130 is rotated and moved from position 4 to position 5.As a result, the cleaning liquid pre-injected into chamber E is flowninto chamber D to clean the magnetic beads. This cleaning liquid passesthrough flow path 115 g to flow into chamber F, wherein waste liquid iscontained (flow path 115 f to chamber H has been squashed and closed).

Next, roller 130 is rotated and moved from position 5 to position 6 sothat buffer liquid pre-injected into chamber G is flown through flowpath 115 e into chamber D (a flow path to chamber F has been squashedand closed by roller 130). Then, chamber D is heated to release the DNAwhich has been captured by the beads. The released DNA is flown withbuffer liquid through flow path 115 f into chamber H to become afinished product.

FIG. 40 is another embodiment of a configuration of FIG. 39. Thedifference from FIG. 39 is that, instead of waste liquid chamber F,circulating flow path 115 h is formed at the drain outlet of reactionchamber D, so that waste liquid is flown back to chamber A. Movements ofroller 130 and inflow and outflow operations of injectants in chambersthrough flow paths are the same as in FIG. 1. Such a configurationcauses the internal pressure of chambers or flow paths not to increaseso that liquid can be transferred smoothly. The space for waste liquidchamber F is no longer necessary, thereby enabling the cartridge forthat space to be reduced.

FIG. 41 illustrates an example of another embodiment, wherein a convexpart as shown in FIG. 39 is not formed in a cartridge. The entirecartridge is formed in a flat shape, wherein the length of roller 130 islimited so that roller 130 moves in the X-Y range on the cartridge. Notethat the same injectants as those in FIG. 39 are contained in chambersA, B, C, E, and G respectively and that chambers D and H also operate inthe same way.

In the above configuration, roller 130 presses chambers A and B downwardfrom above at the left edge of cartridge 100 to the extent that chambersA and B are squashed, wherein the blood and reagent solutionpre-injected into chambers A and B respectively are pushed out in theright direction if roller 130 is rotated and moved in the rightdirection from position 1 to position 2 as shown in FIG. 41.

As a result, the blood pre-injected into chamber A is flown through flowpath 115 a into chamber C, while the reagent solution pre-injected intochamber B is flown through flow path 115 b into chamber C pre-injectedwith magnetic beads, wherein the blood and the reagent solution aremixed.

Next, roller 130 is rotated and moved from position 2 to position 3, sothat the blood and reagent solution mixed in chamber C as well as themagnetic beads which captured DNA are moved through flow path 115 c tochamber D. Magnetic field is applied to chamber D, wherein magneticbeads are captured by the magnetic field.

Next, roller 130 is rotated and moved from position 3 to position 4, sothat flow path 115f is squashed to block the flow into chamber H.Moreover, roller 130 is rotated and moved from position 4 to position 5.As a result, the cleaning liquid pre-injected into chamber E is flowninto chamber D to clean the magnetic beads. This cleaning liquid isflown through circulating flow path 115 h into chamber A (flow path 115f to chamber H has been squashed and closed).

Next, roller 130 is rotated and moved from position 5 to position 6, sothat the buffer liquid pre-injected into chamber G is flown through flowpath 115 e into chamber D (a flow path to circulating path 115 e hasbeen squashed and closed). Then, chamber D is heated to release the DNAwhich has been captured by the beads. The released DNA is flown with thebuffer liquid through flow path 115 f into chamber H to become afinished product.

The downward pressurization for flow paths by means of an external forceoutside the cartridge is not limited to rollers. As shown in FIG. 42,oil, water, air or the like can be pre-injected for pressurization inflow path 115 i so that convex part 161 is pressed by means of anactuator (not illustrated) and tip A′ is expanded to squash flow path115.

FIG. 43 illustrates another embodiment of a mechanism for pressingchambers or flow paths, wherein substrate 120 comprising chambers orflow paths, elastic body 110 with cross sections formed in a convexshape, and rigid body 121 containing elastic body 110 to project theconvex part of this elastic body are combined and wherein the convexpart of elastic body 110 is pressed by a roller, an actuator or the liketo squash the above-mentioned flow paths or chambers. As illustrated,rigid body 121 can also act as a stopper for the actuator.

Note that the number of flow paths 115 leading to each chamber can bearbitrary. Six flow paths are formed in FIG. 44, wherein three convexparts 161 (means of blocking flow paths) as shown in FIG. 42 or FIG. 43are formed to become opening and closing plug valves.

FIG. 45 shows grooved roller 130 a wherein groove 131 is formed oncylindrical roller 130. Positions of convex parts or chambers formed ona cartridge can be combined in various manners.

FIG. 46 shows roller 130 b with a convex part, wherein a convex part issimilarly provided to cylindrical roller 130. Even if a cartridge isflat, an external force can be applied to the cartridge partially as inthe case of the convex part of FIG. 39( b).

As shown in FIG. 47, it is possible to separate the areas into Y1 and Y2wherein the convex part (a) and the convex part (b) are used to applypressure. In this configuration, roller 130 b with a convex part isrotated from the left end and is moved from position X1 to position X2to press out the liquid of chamber A located in area Y1 into chamber Cand also to press the liquid back to chamber B located in area Y2.

Note that the cartridge shown in the above embodiment has the followingproblems under special conditions:

-   -   (1) For example, if genetic amplification is performed, heating        or cooling is required. If a sample combining micro particles        with DNA is used, vibration may be applied to them. However, it        is difficult to transfer heat or vibration to a cartridge formed        of thick materials such as tubes.    -   (2) If a cartridge is formed of a thin glass, a hazard is caused        when solution containing viruses inside the cartridge remains        when the cartridge is disposed of. In addition, cartridges of        glass structure are expensive.

The embodiment shown next is capable of solving these problems. Eventhis chemical reaction cartridge can be heated or cooled rapidly.Sufficient vibration can be transferred to the cartridge. In addition,the influence of heating, cooling or vibration on an adjacent locationis small. The cartridge is also safe and inexpensive.

FIG. 48 illustrates a principal portion of an embodiment concerning sucha cartridge. This cartridge has a structure which is suitable forgenetic amplification based on the PCR method or for using a samplewherein magnetic particles are combined with DNA. Note that thedescriptions below deal with the characteristics only. Features otherthan the characteristics are the same as those of the above embodiment,and therefore, explanations of such features are omitted.

In FIG. 48, 200 a is an action means to allow its tip to contact withthin elastic film 110 a of the cartridge and to heat or cool a sample inchamber A (for example, reaction chamber 113 of FIG. 4( b)) by means ofa Peltier element or the like, or to provide vibration by means of avoice coil or a piezoelement. In the following embodiment, this actionmeans is called an external jig. Note that the sample means DNA,magnetic particles or the like as well as solution.

The forming part of elastic film 110 a is local and is limited to theupper part of chamber A with which external jig 200 a contacts. Elasticfilm 110 a of that part is thinner than the other parts of the elasticbody and is formed with a thickness of 1 mm or less. The optimumthickness “t” is, for example, 0.1 to 1 mm.

Next, operations in such a configuration are explained. A sample isinjected into chamber A of the cartridge. A flow path or the like in thecartridge is blocked to raise the internal pressure of chamber A.Elastic film 110 a remains in tension.

Note that internal pressure is not limited to a local portion of chamberA only. It can be raised across chambers and flow paths in thecartridge.

A tip of external jig 200 a is pressed and adhered to the surface ofelastic film 110 a with raised internal pressure. Depending ontreatments, the sample can be heated, cooled, or vibrated.

In a genetic amplification treatment based on the PCR method, heatingand cooling are repeated. Since elastic film 110 a is thin and heatingand cooling are directly applied to the sample through adhered elasticfilm 110 a, the response is far quicker than in conventional indirectheating and cooling methods.

In this manner, heating and cooling or vibration can be applied to thesample if only an elastic body on the upper part of a target chamber isformed of a thin film of 1 mm or less, to which external jig 200 a isadhered. Since heating and cooling are directly applied only to thesample and rarely affect other portions with almost no transmittance,high speed response can be achieved. Also, vibration is directly appliedonly to the sample and rarely affects other portions with almost notransmittance.

Note that the present invention is not limited to the above embodiments.For example, as shown in FIG. 49, internal pressure of chamber A may begenerated by the pressing (or introduction) of an external jig. In thiscase, entrance flow path 115 j and exit flow path 115 k, which areformed in the same direction from chamber A, are squashed simultaneouslyby roller 130 (to act as a plug valve) to seal chamber A, and thenexternal jig 200 a is pressed to the elastic film, thereby raising theinternal pressure of chamber A.

Notch 110 b may be formed in the surrounding elastic portions of an areawith which external jig 200 a contacts, as shown in FIG. 50( a), inorder to reduce the transmittance of heat or vibration to otherportions. Or, as shown in FIG. 50( b), filling member 110 c made of heatinsulation materials or vibration insulation materials may be buriedinto the notches.

Or, as shown in FIG. 51, elastic film 110 a may be formed of atransparent film. If a transparent film is used, it is possible toobserve fluorescent light during DNA hybridization through the window(elastic film 110 a) of the transparent film by means of readingapparatus 400. If a sample is heated, laser can be emitted through thewindow instead of using an external jig.

Unless elastic film 110 a becomes wrinkled or does not contain bubbles,the internal pressure of a chamber can almost be atmospheric pressure.

For capturing DNA, silica beads or the like can be used for magneticbeads. In this case, filters smaller than beads can be used to capturethe beads themselves.

The vertical relationship between a cartridge and an external jig may beopposite to that of the embodiment. In other words, the top and thebottom of the cartridge may be reversed so that the external jig ispressed against elastic film 110 a from below.

Application of pressure to an elastic body is not limited topressurization to the entire range of the cartridge by means of a rolleras shown in the above embodiments. An external force can be applied fromoutside the container to partially close a flow path, a chamber or both,so that fluid substance in the flow path or in the chamber will be movedor blocked.

A pump or a valve to play such a role is not limited to an externalforce. An external pump outside a cartridge or an internal valve made ofshape-memory alloy or the like may be used.

Since cartridges of the above configurations are sealed and disposable,they have a safe structure against viruses or dangerous drugs. Inaddition, these cartridges are very useful from a practical point ofview because they allow prescribed protocols for chemical reactions orthe like to be achieved easily without differences among operators.

1. A chemical reaction cartridge for application in connection withperforming chemical reactions of samples, comprising: a containerincluding a rigid substrate and an elastic body adhered to a surface ofthe substrate, and a plurality of chambers connected through a pluralityof flow paths are formed in the elastic body, wherein the elastic bodyis configured to be partially deformed by a roller, wherein in saidelastic body some flow paths and some chambers are configured to beblocked by said roller, while simultaneously, other flow paths and otherchambers are configured to be un-blocked, wherein at least two said flowpaths and two said chambers are in parallel with each other with respectto a lengthwise direction of said elastic body, wherein said at leasttwo said flow paths are spaced apart widthwise and connected at one endthereof, wherein application of external force from said roller causessimultaneous fluid flow in opposite directions in said at least two saidflow paths, and wherein holes are provided at plural positions of thecartridge for position determination of the cartridge to determine anaccurate position when said external force is applied.
 2. The chemicalreaction cartridge of claim 1, wherein reaction liquid, a reactionsubstance or a sample is injected or fixed prior to reaction in at leastone of said two or more chambers.
 3. The chemical reaction cartridge ofclaim 2, wherein an entrance is provided to inject said reaction liquid,said reaction substance or said sample so that said entrance is sealedwith adhesion or fusion.
 4. The chemical reaction cartridge of claim 3,wherein said entrance is provided to include said sample and whereinsaid entrance has a part concave from the surface of said containertowards the inside so that injected said sample will not flow out ofsaid container.
 5. The chemical reaction cartridge of claim 1, wherein atarget of said chemical reaction is an inorganic substance, organicsubstance, a biopolymer or a cell in performing treatments such asmixture, synthesis, dissolution, separation, detection or the like. 6.The chemical reaction cartridge of claim 1, wherein said forceapplication means presses said fluid substances used in said chemicalreaction out of the cartridge.
 7. The chemical reaction cartridge ofclaim 1, wherein the surface of said elastic body is essentially flat,in a concave shape or in a convex shape.
 8. The chemical reactioncartridge of claim 1, wherein said elastic body is formed of a pluralityof layers, each of which has a chamber being linked through a flow path.9. The chemical reaction cartridge of claim 1, wherein a part or a wholeof said elastic body is transparent.
 10. The chemical reaction cartridgeof claim 1, wherein said flow path or said chamber is formed with itscorners not in a right angle but in a curved shape.
 11. The chemicalreaction cartridge of claim 1, wherein a one-way valve with a movableportion is formed at an outlet of said flow path or said chamber, saidoutlet closes when a pressure is applied, or said outlet acts as a valveto expand when the pressure is applied.
 12. The chemical reactioncartridge of claim 1, wherein said flow path or said chamber is formedso that it is expanded in a perpendicular direction to a length of thecartridge upon the application of the external force by said forceapplication means.
 13. The chemical reaction cartridge of claim 1,wherein the surface of said flow path or said chamber is hydrophobic orhydrophilic.
 14. The chemical reaction cartridge of claim 1, wherein thesurface of said flow path or said chamber is coated withfluorine-containing polymers.
 15. The chemical reaction cartridge ofclaim 1, wherein a projection for separation and disturbance or aprojection for homogenization is provided in said chamber.
 16. Thechemical reaction cartridge of claim 1, wherein a conductor is providedin said chamber to exchange input and output signals of a reactionsubstance such as voltage, electric current, heat generation or the likewith external entities or wherein said chamber is formed to enable theinsertion of said conductor.
 17. The chemical reaction cartridge ofclaim 1, wherein a transparent member is formed in said chamber to allowoptical detection.
 18. The chemical reaction cartridge of claim 1,wherein a waste liquid reservoir is formed as one of said chambers tocontain waste liquid and wherein solidification reaction agent isinjected into said waste liquid reservoir to solidify waste liquid. 19.The chemical reaction cartridge of claim 1, wherein a metal is arrangedin said chamber to transmit temperature changes for the purpose ofperforming genetic PCR amplification or a Peltier heater is arranged insaid chamber to change temperature in said chamber.
 20. The chemicalreaction cartridge of claim 1, wherein said elastic body is aviscoelastic body or a plastic body.
 21. The chemical reaction cartridgeof claim 1, wherein a cartridge end to first engage with a cylindricalroller intended to move said fluid substance is formed in a taper shape.22. The chemical reaction cartridge of claim 1, wherein, when two ormore elastic bodies are combined to comprise said cartridge; aprojection, a concave part or both the projection and the concave partare included in combined faces of said two or more elastic bodies tothereby join said combined faces in a sealed manner.
 23. The chemicalreaction cartridge of claim 1, wherein a thin elastic film is formed ina part of said elastic body to allow the contact or introduction of anaction means outside said cartridge to provide heating, cooling,vibration, or light to a sample in said chamber.
 24. The chemicalreaction cartridge of claim 23, wherein said thin elastic film has athickness of 1 mm or less.
 25. The chemical reaction cartridge of claim23, wherein the internal pressure of said chamber covered with said thinelastic film is equal to or greater than the pressure external to saidchamber when said action means is contacted or introduced.
 26. Thechemical reaction cartridge of claim 23, wherein a notch has heatinsulation materials or vibration insulation materials therein, and saidnotch is formed in an elastic portion which surrounds said thin elasticfilm.
 27. A chemical reaction system for application in connection withperforming chemical reaction of samples, comprising: a cartridge and anexternal force application means; wherein two or more chambers areprovided in the cartridge for performing the chemical reaction of thesamples and are linked through flow paths in a container, at least apart of which is composed of an elastic body which contains said two ormore chambers, said elastic body is configured to be partially deformed,wherein in said elastic body some flow paths or some chambers areconfigured to be blocked by said force application means, whilesimultaneously, other flow paths and other chambers are configured to beun-blocked, wherein at least two said flow paths and two said chambersare in parallel with other each with respect to a lengthwise directionof said elastic body, wherein said at least two said flow paths arespaced apart widthwise and connected at one end thereof, whereinapplication of external force from said external force application meanscauses simultaneous fluid flow in opposite directions in said at leasttwo said flow paths, wherein a first area is provided to which saidexternal force is to be applied, wherein a second area is provided towhich said external force is not to be applied, and wherein holes areprovided at plural positions of the cartridge for position determinationof the cartridge to determine an accurate position when said externalforce is applied.
 28. The chemical reaction system of claim 27, whereinsaid external force application means is a roller or an actuator, and acontact face configured to contact said external force applicationmeans; wherein a cartridge or both of said contact face and saidcartridge is formed in a convex shape in said area to which saidexternal force is applied by said external force application means. 29.The chemical reaction system of claim 27, wherein said external forceapplication means is a roller with a prescribed width or an actuator andwherein the width of said roller is limited to the width of an area forpressing said cartridge.
 30. The chemical reaction system of claim 27,further comprising: a substrate wherein said flow paths or said chambersare formed; and a rigid body including said elastic body formed thereonso that a convex part of said elastic body is projected, wherein saidconvex part of said elastic body is configured to be pressed to squashsaid flow paths or chambers and a portion of a surface of said elasticbody is formed in a convex shape.
 31. The chemical reaction system ofclaim 27, wherein flow paths for linking chambers are configured to beopened or closed due to liquid pressure or air pressure in saidcartridge, which is changed by said external force application means.32. The chemical reaction cartridge of claim 17, wherein a transparentmember is buried in one of said plurality of chambers to allow opticaldetection.
 33. The chemical reaction cartridge of claim 1, wherein saidholes penetrate the cartridge.
 34. The chemical reaction cartridge ofclaim 1, wherein said cartridge has four corners, and wherein said holespenetrate the cartridge at said four corners.